Formulating low solubility therapeutic compounds (e.g., Bioclassification II and IV compounds) can be challenging because of variability in the physical properties of the compound. A formulation which results in acceptable pharmaceutical unit doses using one lot of active compound may produce unacceptable pharmaceutical unit doses with another lot of active compound. In some cases, the compound may be highly cohesive and adhesive which presents a number of processing challenges.
Problems associated with formulations include poor granule quality, poor weight uniformity among doses, and tablets that have a surface damage as a result of challenges during granule compression. Variable product characteristics and density variations resulting from previously known methods may make the product's commercial use impractical.
In recent years, there has been a steady increase in the number of low solubility compounds in drug development. For example, up to approximately 90% of new chemical entities can be categorized as BCS class II or IV compounds. In contrast, more than 50% of marketed drugs are classified as highly soluble. Thus, it is clear that poor compound solubility is a major hurdle for formulators of new chemical entities. Oral bioavailability of insoluble compounds may be improved by optimizing the API's chemical (e.g., salt formation) and physical (e.g., particle size reduction through milling) properties. However, the increased number of compounds in development and the shortened timelines for formulation development require a more efficient approach using computational tools in place of or in addition to empirical approaches typically employed to study API effect on bioavailability, such as in vivo studies in animal models. Computational tools may also provide a mechanistic link between API properties and bioperformance.
Absorption estimates such as the maximum absorbable dose calculation or the absorption potential proposed by Dressman et al. can be used to link the solubility of compound to the expected extent of oral absorption. Such estimates would appear suitable for early decisions on API phase selection as far as overall exposure is concerned. However, formulation development is frequently driven by specific pharmacokinetic and pharmacodynamic needs (e.g., rapid solubilization of drugs for fast onset of action), in which case more detailed models are needed to account for the rate of dissolution as well as the linkage between absorption and pharmacokinetic profile. Similarly, when trying to understand effect of API bulk properties on formulation bioperformance, models that can account for the effect of API on dissolution rate are needed to guide formulation efforts.
Thus, there is a need for a method to deliver drugs that minimize or overcome the above-referenced problems. There is also a need for a simple manufacturing process utilizing existing conventional equipment to lower manufacturing costs.